Method of therapeutically treating a warm blooded animal afflicted with an autoimmune disease

ABSTRACT

The invention provides a method of therapeutically treating a warm blooded animal afflicted with an autoimmune disease such as rheumatoid arthritis. In one variant, this is accomplished by administering an ethereally monosubstituted monosaccharide having the general formula M 1  --O--Y, and/or an ethereal monosubstitution of monosaccharide derivatives having the general formula M 2  --O--Y, and/or pharmaceutically acceptable organic acid and inorganic acid salts thereof as defined hereinafter. In a preferred variant, a synergistic mixture is used containing one or more of the foregoing compounds as a first ingredient and an additional compatible substance as a second ingredient which is effective to therapeutically treat autoimmune diseases in warm blooded animals. The invention further provides a novel synergistic composition for therapeutically treating warm blooded animals afflicted with an autoimmune disease which consists essentially of the aforementioned first and second ingredients.

This is a divisional of U.S. application Ser. No. 473,264 filed Mar. 14,1983, which is a continuation of U.S. application Ser. No. 234,505,filed Feb. 17, 1981, now abandoned, which is a continuation of U.S.application Ser. No. 122,742, filed Feb. 19, 1980, now abandoned, whichwas a continuation of U.S. application Ser. No. 845,788, filed Oct. 26,1977, now abandoned.

THE BACKGROUND OF THE INVENTION

1. The Field of the Invention

The present invention is concerned with a method of therapeuticallytreating warm blooded animals afflicted with an autoimmune disease. Inanother variant, the invention further relates to a synergisticcomposition for therapeutically treating warm blooded animals afflictedwith an autoimmune disease.

2. The Prior Art

Warm blooded animals in general, and especially man and lower mammals,often contract autoimmune-type diseases which are well known andrecognized by the medical profession. The autoimmune diseases appear toinvolve a malfunctioning of the natural immune system wherein theafflicted animal develops immunity to its own cells or tissues, such asthe synovial membrane of the joints in rheumatoid arthritis. While thepresent invention is not limited to the therapeutic treatment thereof,some specific examples of autoimmune diseases include rheumatoidarthritis, rheumatic fever, eczema and lupus erythematosis.

A wide variety of therapeutic treatments have been proposed heretoforefor use in treating the aforementioned autoimmune diseases. Examples ofsome of the more common prior art drugs include (1) aspirin and otherrelated pharmaceutically acceptable lower carboxylic acid salicylateswherein the carboxylic acid contains 1-8 and preferably 2-4 carbonatoms, for the treatment of rheumatoid arthritis and rheumatic fever,(2) phenylbutazone and indomethacin as a treatment for rheumatoidarthritis (c) adrenocorticosteroids for the treatment of rheumatoidarthritis, rheumatic fever and lupus erythematosis, and (4) levamisolefor the treatment of rheumatoid arthritis, eczema, and lupuserythematosis. However, these prior art medications have not beenentirely satisfactory or generally effective heretofore. As a result, asubstantial percentage of the population continues to be afflicted withan autoimmune disease such as rheumatoid arthritis.

In the view of the foregoing, it is apparent that the prior art has longsought an entirely satisfactory method and composition fortherapeutically treating autoimmune diseases in warm blooded animals.However, in spite of the long standing and great need therefor, such amethod and composition were not available prior to the presentinvention.

THE SUMMARY OF THE INVENTION INCLUDING CERTAIN OBJECTS THEREOF

In accordance with one variant of the invention, autoimmune diseases inwarm blooded animals are therapeutically treated by administering atherapeutically effective amount of an ethereally monosubstitutedmonosaccharide having the general formula M₁ --O--Y, and/or an etherealmonosubstitution of monosaccharide derivatives having the generalformula M₂ --O--Y, and/or a pharmaceutically acceptable organic acid orinorganic acid salt thereof. In practicing another variant of theinvention, a synergistic composition containing one or more of theforegoing compounds as a first ingredient and a second therapeuticallyactive ingredient for treating autoimmune diseases is administered tothe warm blooded animals. Novel synergistic compositions containing theaforementioned first and second ingredients are also provided for use inpracticing the latter method of the invention. The aforementionedmethods and synergistic compositions are very effective in overcomingthe longstanding problems and deficiencies of the prior art discussedabove.

It is an object of the present invention to provide a novel method oftherapeutically treating a warm blooded animal afflicted with anautoimmune disease.

It is a further object to provide a novel method of therapeuticallytreating autoimmune diseases in warm blooded animals by administering asynergistic combination of drugs.

It is still a further object to provide a synergistic compositioncontaining two or more therapeutically active ingredients which isespecially useful in practicing the method of the invention.

Still other objects and advantages of the invention will be apparent tothose skilled in the art upon reference to the following detaileddescription and the specific examples.

THE DETAILED DESCRIPTION OF THE INVENTION INCLUDING PRESENTLY PREFERREDVARIANTS THEREOF

In practicing the presently preferred variant of the method of theinvention, warm blooded animals afflicted with an autoimmune disease aretreated by administering a therapeutically effective amount of asubstance which comprises at least one ethereally monosubstitutedmonosaccharide having the general formula M₁ --O--Y, and/or at least oneethereal monosubstitution of monosaccharide derivatives having thegeneral formula M₂ --O--Y, and/or at least one pharmaceuticallyacceptable organic acid or inorganic acid salt of the foregoingcompounds. In practicing another presently preferred variant of themethod of the invention, autoimmune diseases in warm blooded animals aretherapeutically treated by administering a synergistic compositioncontaining one or more of the aforementioned compounds as a firstingredient, and as a second ingredient, an additional substance which istherapeutically effective to treat the autoimmune disease whenadministered alone to the warm blooded animal and which istherapeutically compatible with the first ingredient. In accordance witha further presently preferred variant of the invention, synergisticcompositions containing the aforementioned first and second ingredientsare provided which are especially useful in practicing the latter methodof the invention.

In the foregoing general formulae, M₁ is the residue of a nonderivatizedmonosaccharide selected from the group consisting of pentoses, hexosesand heptoses, and M₂ is the residue of a monosaccharide selected fromthe group consisting of pentoses, hexoses and heptoses which has beenderivatized with (a) one or more alcohols containing 1-18 carbon atomsand preferably 1-4 carbon atoms to produce an ether group at one or moreavailable hydroxyl groups or residua, (b) one or more aldehydescontaining 1-18 carbon atoms and preferably 1-4 carbon atoms to producesingle or multiple acetal groups at one or more available hydroxylgroups or residua, (c) one or more ketones containing 1-18 carbon atomsand preferably 1-4 carbon atoms to produce single or multiple ketalgroups at one or more available hydroxyl groups or residua, or (d) oneor more organic acid residua containing 1-18 carbon atoms and preferably1-4 carbon atoms to produce ester groups at one or more availablehydroxyl groups or residua. The above alcohols, aldehydes, ketones andacids may be either open or closed chain compounds, saturated orunsaturated, and substituted or unsubstituted. In each instance, Y isselected from the group consisting of cyclic monovalentnitrogen-containing organic radicals and residua free of oxygen attachedonly to a ring carbon atom and derived from a substance other than amonosaccharide, and monovalent organic radicals and residua having thegeneral formula ##STR1## wherein R₁ is a divalent organic radical havinga carbon chain length of about 1-7 carbon atoms and R₂ and R₃ areselected from the group consisting of --H, --OH, --SH, halogen andmonovalent organic radicals and residua having a carbon chain length ofabout 1-7 carbon atoms. When R₂ or R₃ is halogen, the halogen may be F,Cl, Br, or I, of which Cl and Br is usually preferred. The organicradical R₁, and R₂ and R₃ when they are organic radicals, may bebranched or unbranched carbon chains and may be saturated orunsaturated, and when saturated, the unbranched and/or branched carbonchains may contain one or more double or triple carbon-to-carbon bonds.The unbranched and/or branched carbon chains of R₁, R₂ and R₃ may besubstituted or unsubstituted, and when substituted, one or moresubstituents may be present, such as --OH, --SH, halogen (F, Cl, Brand/or I), branched or unbranched and saturated or unsaturatedhydrocarbon radicals containing 1-7 and preferably 1-3 carbon atoms,--OR₄ and/or --SR₄ radicals, wherein R₄ is a branched or unbranched andsaturated or unsaturated hydrocarbon radical containing 1-7 andpreferably 1-3 carbon atoms, carboxylic acid residua containing 1-7 andpreferably 1-3 carbon atoms, and amino groups and aminohydrocarbonradicals containing 1-7 and preferably 1-3 carbon atoms. Preferably R₁is a hydrocarbon radical having a carbon chain length of 1-3 or 1-4carbon atoms and R₂ and R₃ are individually selected from the groupconsisting of hydrogen and/or hydrocarbon radicals having carbon chainlengths of 1-3 or 1-4 carbon atoms.

Examples of compounds from which cyclic organic radicals and residua arederived include (a) monovalent nitrogen containing saturated,unsaturated or aromatic carbocyclic compounds containing about 4-8carbon atoms in the ring and preferably about 5-6 carbon atoms in thering and at least one nitrogen atom attached thereto or to an organosubstituent thereon, (b) heterocyclic organic compounds containing about3-8 carbon atoms in the ring and at least one ring nitrogen atom and (c)derivatives of the foregoing compounds wherein at least one substituentis present, such as --OH, --SH, halogen (F, Cl, Br and/or I), branchedor unbranched and saturated or unsaturated hydrocarbon radicalscontaining 1-7 and preferably 1-3 carbon atoms, --OR₅ and/or --SR₅radicals wherein R₅ is a branched or unbranched and saturated orunsaturated hydrocarbon radical containing 1-7 and preferably 1-3 carbonatoms, carbocyclic acid residua containing 1-7 and preferably 1-3 carbonatoms, and amino groups and aminohydrocarbon radicals containing 1-7 andpreferably 1-3 carbon atoms. The aforementioned cyclic organic radicalsand residua should be free of oxygen attached only to a ring carbon atomand also should be derived from a substance other than a monosaccharide.

The nonderivatized monosaccharide residue M₁ may exist in an open chainor cyclic form illustrated by the following general formulae: ##STR2##wherein X₁ and Z₁ are H, OH and/or hydroxyalkyl groups containing up to3 carbon atoms, Y represents the same organic radicals and residua asaforementioned, and one of the OH groups, X₁ or Z₁ in each formula isreplaced by --O--Y. The above general formulae (b) and (c) illustratethe pentacyclic and hexacyclic forms of the various isomers of thepentoses hexoses and heptoses, the relative spatial configuration of the--H, and --OH groups about the rings, and the monosubstitution thereofin accordance with one presently preferred variant of the invention. Thehydroxyl group of the hemiacetal or hemiketal linkage may assume an α ora β configuration and the compounds may be in the form of anomers ormixtures of anomers.

The derivatized monosaccharide residue M₂ may exist in an open chain orcyclic form illustrated by the following general formulae: ##STR3##wherein X₂ and Z₂ are H, --OH, hydroxyalkyl, alkoxyl and/or alkoxyalkylgroups containing up to 3 carbon atoms, W is H, alkyl, alkenyl, cyclicalkane or cyclic aromatic groups containing 1-18 and preferably 1-6carbon atoms or acyl groups containing 1-18 and preferably 1-4 carbonatoms, Y represents the same organic radicals and residua asaforementioned, and one of the OW groups X₂ or Z₂ in each formula isreplaced by --O--Y. The above general formulae illustrate the variousisomers of the pentoses, hexoses and heptoses, the relative spatialconfiguration of the --H and --OH groups about the ring and thederivatization thereof in accordance with one presently preferredvariant of the invention. The hydroxyl or alkoxyl residue of thehemiacetal or hemiketal linkage may assume an α or a β configuration,and the derivatized monosaccharide may be in form of anomers or mixturesof anomers.

The configuration of the various isomers and derivatives of thepentoses, hexoses and heptoses are well known to those skilled in thisart and numerous reference books are available on the subject, theteachings of which are incorporated herein by reference, for exampleTextbook of Biochemistry, 4th Edition. by West et al (1966) and TheMonosaccharides by Stanek, Cerny, Kocourek and Pacak (1963). The priorart discloses, for example, a total of eight open chain isomers for thereducing hexoses, and an even larger number of open chain isomers forthe reducing heptoses. Either the dextrorotatory or D-series or thelevorotatory or L-series of the pentoses, hexoses and heptoses may beused in practicing the invention, but it is usually preferred to use theD-series. The hexoses often give the best results and especiallyD-talose, D-galactose, L-galactose, D-idose, D-gulose, D-mannose,D-glucose, L-glucose, D-altrose and D-allose. The aforementionedpentoses, hexoses and heptoses may be derivatized at one or more of thehydroxyl groups, and is then ethereally substituted at one remainingavailable reactive position or positions. The ethereal substitution ofcertain available reactive positions of specific monosaccharidederivatives results in more therapeutically active or less toxiccompounds. For instance, substitution of the 1-O- and 3-O-positions ofglucose and the 6-O-position of galactose results in especially valuablecompounds. Additionally, the ethereal substitution of the 3-O-positionof 1,2-O-isopropylidene-D-glucofuranose or1,2:5,6-di-O-isopropylidene-D-glucofuranose and the 6-O-position of1,2-O-isopropylidene-D-galactopyranose or1,2:3,4-di-O-isopropylidene-D-galactopyranose results in especiallyvaluable compounds.

The following substituents, i.e., Y in the aforementioned generalformulae M₁ --O--Y or M₂ --O--Y, may be ethereally substituted on any ofthe available reactive positions of the various isomers of the pentoses,hexoses and heptoses of M₁ or M₂ to produce nontoxic compounds havingexceptional activity for the purposes of the present invention:

-(n-propylamino),

-(N',N'-dimethylamino-n-propyl),

-(N',N'-dimethylaminoisopropyl),

-(N'-methylpiperidyl),

-(N',N'-dimethylaminoethyl),

-(N',N'-diethylaminoethyl),

-(2',N',N'-trimethylamino-n-propyl),

-dimethylamino,

-(N',N'-dimethylaminomethyl),

-(N',N'-dimethylaminopropyl),

-(N',N'-dimethylamino-iso-butyl),

-(N',N'-dimethylamino-n-butyl),

-(N',N'-dimethylamino-iso-pentyl),

-(N',N'-dimethylaminopentyl),

-(N'-methylamino-n-propyl),

-(N'-methyl-N'-ethylamino-n-propyl),

-(N',N'-diethylamino-n-propyl),

-(amino-iso-propyl),

-(N'-ethylamino-n-propyl),

-(N'-propylamino-n-propyl),

-(N',N'-iso-propylamino-n-propyl),

-(1',2'-ethylamino-n-propyl),

-(1'-n-propylpyrrolidyl),

-(1'-n-propylpiperidyl),

-piperidyl, and

-(N',N'-dimethylamino-sec-butyl).

Of the foregoing, -(N',N'-dimethylamino-n-propyl) is presently preferredas Y in the formulae M₁ --Y--O and M₂ --O--Y and especially whensubstituted in the 1-O- or 3-O- position of glucose or in the 6-O-position of galactose, or when substituted in the 3-O- position of1,2-O-isopropylidene-D-glucofuranose or1,2:5,6-di-O-isopropylidene-D-glucofuranose or the 6-O- position of1,2-O-isopropylidene-D-galactopyranose or1,2:3,4-di-O-isopropylidene-D-galactopyranose.

The following compounds of the general formula M₁ --O--Y have been foundto have exceptional activity for use in the present invention:

3-O-3'-(n-propylamino)-glucose,

3-O-3'-(N',N'-dimethylamino-n-propyl)-glucose,

3-O-4'-(N-methyl piperidyl)-glucose,

3-O-2'-(N',N'-dimethylaminoethyl)-glucose,

3-O-2'-(N',N'-diethylaminoethyl)-glucose,

3-O-3'-(2',N',N'-trimethylamino-n-propyl)-glucose,

α-N',N'-dimethylaminoisopropyl-glucoside,

6-O-3'-(N',N'-dimethylamino-n-propyl)-galactose,

3-O-2'-(N',N'-dimethylaminopropyl)-glucose,

6-O-2'-(N',N'-dimethylaminopropyl)-galactose, and

pharmaceutically acceptable organic acid and inorganic acid saltsthereof. The D-series of these compounds are preferred. Species of theforegoing compounds which are presently preferred as follows:

3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucopyranose,

3-O-4'-(N-methyl piperidyl)-D-glucopyranose,

3-O-2'-(N',N'-dimethylaminoethyl)-D-glucopyranose,

3-O-3'-(2',N',N'-trimethylamino-n-propyl)-D-glucopyranose,

α-N',N'-dimethylaminoisopropyl-D-glucoside,

6-O-3'-(N',N'-dimethylamino-n-propyl)-D-galactopyranose,

3-O-2'-(N',N'-dimethylaminopropyl)-D-galactopyranose,

6-O-2'-(N',N'-dimethylaminopropyl)-D-galactopyranose, and

pharmaceutically acceptable organic acid and inorganic acid saltsthereof.

Additional compounds of the general formula M₁ --O--Y, wherein Y is##STR4## which may be used in practicing the invention are listed below:

    ______________________________________                                                      Substituent                                                     Monosaccharide Residue                                                                      (Y)                                                             M.sub.1       R.sub.1      R.sub.2  R.sub.3                                   ______________________________________                                        3-O--D-glucofuranose                                                                        3'-n-propyl  H        methyl                                    "             "            ethyl    "                                         "             "            H        ethyl                                     "             2'-iso-propyl                                                                              methyl   methyl                                    "             3'-1,2-propenyl                                                                            "        "                                         "             sec-butyl    "        "                                         "             3'-butyl     "        "                                         "             2'-ethyl     H        H                                         "             methyl       H        H                                         6-O--D-galactopyranose                                                                      3'-n-propyl  H        methyl                                    "             "            ethyl    "                                         "             "            H        ethyl                                     "             3'-1,2-propenyl                                                                            methyl   methyl                                    "             2'-iso-propyl                                                                              "        "                                         "             sec-butyl    "        "                                         "             3'-butyl     "        "                                         "             2'-ethyl     H        H                                         "             methyl       H        H                                         ______________________________________                                    

Still other compounds of the general formula M₁ --O--Y, wherein Y iscyclic monovalent nitrogen-containing organic radical or residue, whichmay be used in the method of the invention are as follows:

    ______________________________________                                                     Substituent                                                                   (Y)                                                                                          Substituent                                       Monosaccharide Residue      on the                                            M.sub.1        Cyclic Radical                                                                             Cyclic Radical                                    ______________________________________                                        3-O--D-glucofuranose                                                                         4'-piperidyl H                                                 "              3'-piperidyl methyl, H                                         "              2'-piperidyl methyl, H                                         "              3'-pyrrolidyl                                                                              methyl, H                                         "              2'-pyrrolidyl                                                                              methyl, H                                         6-O--D-galactopyranose                                                                       4'-piperidyl H                                                 "              3'-piperidyl methyl, H                                         "              2'-piperidyl methyl, H                                         "              3'-pyrrolidyl                                                                              methyl, H                                         "              2'-pyrrolidyl                                                                              methyl, H                                         ______________________________________                                    

The following compounds of the general formula M₂ --O--Y haveexceptional wide spectrum activity and other valuable properties:

3-O-3'-(n-propylamino)-1,2-O-isopropylidene-D-glucofuranose,

3-O-3'-(N',N'-dimethylamino-n-propyl)-1,2-O-isopropylidene-D-glucofuranose,

3-O-4'-(N'-methylpiperidyl)-1,2-O-isopropylidene-D-glucofuranose,

3-O-2'-(N',N'-dimethylaminoethyl)-1,2-O-isopropylidene-D-glucofuranose,

3-O-2'-(N',N'-diethylaminoethyl)-1,2-O-isopropylidene-D-glucofuranose,

3-O-3'-(2',N',N'-trimethylamino-n-propyl)-1,2-O-isopropylidene-D-glucofuranose,

3-O-2'-(N',N'-dimethylaminopropyl)-1,2:5,6-di-O-isopropylidene-D-glucofuranose,

3-O-2'-(N',N'-dimethylaminopropyl)-1,2-O-isopropylidene-D-glucofuranose,

6-O-3'-(N',N'-dimethylamino-n-propyl)-1,2-O-iospropylidene-D-galactopyranose,

6-O-2'-(N',N'-dimethylaminopropyl)-1,2-O-isopropylidene-D-galactopyranose,

3-O-3'-(n-propylamino)-1,2:5,6-di-O-isopropylidene-D-glucofuranose,

3-O-3'-(N',N'-dimethylamino-n-propyl)-1,2:5,6-di-O-isopropyidene-D-glucofuranose,

3-O-4'-(N'-methylpiperidyl)-1,2:5,6-di-O-isopropylidene-D-glucofuranose,

3-O-2'-(N',N'-dimethylaminoethyl)-1,2:5,6-di-O-isopropylidene-D-glucofuranose,

3-O-2'-(N',N'-diethylaminoethyl)-1,2:5,6-di-O-isopropylidene-D-glucofuranose,

3-O-3'-(2',N',N'-trimethylamino-n-propyl)-1,2:5,6-di-O-isopropylidene-D-glucofuranose,

6-O-3'-(N',N'-dimethylamino-n-propyl)-1,2:3,4-di-O-isopropylidene-D-galactopyranose,

6-O-2'-(N',N'-dimethylaminopropyl)-1,2:3,4-di-O-isopropylidene-D-galactopyranose,

α-N',N'-dimethylamino-iso-propyl-2,3:5,6-di-O-isopropylidene-D-glucofuranoside,and organic and inorganic acid salts thereof.

Additional compounds of the general formula M₂ --O--Y, wherein Y is##STR5## which may be used in the method of the invention are listedbelow:

    ______________________________________                                                        Substituent                                                   Monosaccharide Residue                                                                        (Y)                                                           M.sub.1         R.sub.1     R.sub.2  R.sub.3                                  ______________________________________                                        3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-n-propyl H        methyl                                    .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   "           ethyl    "                                         .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   "           H        ethyl                                     .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   2'-iso-propyl                                                                             methyl   methyl                                    .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-1,2-propenyl                                                                           "        "                                         .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   sec-butyl   "        "                                         .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-butyl    "        "                                         .sub.--D-glucofuranose                                                       3- .sub.--O-- 1,2- .sub.--O--isopropylidene-                                                  2'-ethyl    H        H                                         .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   methyl      H        H                                         .sub.--D-glucofuranose                                                       6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-n-propyl H        methyl                                    .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   "           ethyl    "                                         .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   "           H        ethyl                                     .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-1,2-propenyl                                                                           methyl   methyl                                    .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   2'-iso-propyl                                                                             "        "                                         .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   sec-butyl   "        "                                         .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-butyl    "        "                                         .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   2'-ethyl    H        H                                         .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   methyl      H        H                                         .sub.--D-galactopyranose                                                     3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       3'-n-propyl H        methyl                                   propylidene- .sub.--D-gluco                                                   furanose                                                                      3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       "           ethyl    "                                        propylidene- .sub.--D-gluco                                                   furanose                                                                      3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       "           H        ethyl                                    propylidene- .sub.--D-gluco                                                   furanose                                                                      3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       2'-iso-propyl                                                                             methyl   methyl                                   propylidene- .sub.--D-gluco                                                   furanose                                                                      3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       3'-1,2-propenyl                                                                           "        "                                        propylidene- .sub.--D-gluco                                                   furanose                                                                      3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       sec-butyl   "        "                                        propylidene- .sub.--D-gluco                                                   furanose                                                                      3-  .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                      3'-butyl    "        "                                        propylidene- .sub.--D-gluco                                                   furanose                                                                      3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       2'-ethyl    H        H                                        propylidene- .sub.--D-gluco                                                   furanose                                                                      3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       methyl      H        H                                        propylidene- .sub.--D-gluco                                                   furanose                                                                      6- .sub.--O--1,2:3,4-di- .sub.--O--iso-                                                       3'-n-propyl H        methyl                                   propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:3,4-di- .sub.--O--iso-                                                       "           ethyl    "                                        propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:3,4-di- .sub.--O--iso-                                                       "           H        ethyl                                    propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:3,4-di- .sub.--O--iso-                                                       3'-1,2-propenyl                                                                           methyl   methyl                                   propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:3,4-di- .sub.--O--iso-                                                       2'-iso-propyl                                                                             "        "                                        propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.-- O--1,2:3,4-di- .sub.--O--iso-                                                      sec-butyl   "        "                                        propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:3,4-di- .sub.--O--iso-                                                       3'-butyl    "        "                                        propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:3,4-di- .sub.--O--iso-                                                       2'-ethyl    H        H                                        propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:3,4-di- .sub.--O--iso-                                                       methyl      H        H                                        propylidene- .sub.--D-                                                        galactopyranose                                                               ______________________________________                                    

Still other compounds of the general formula M₂ --O--Y wherein Y is acyclic monovalent nitrogen-containing organic radical or residue, whichmay be used in the method of the invention are as follows:

    ______________________________________                                                      Substitutent                                                                  (Y)                                                                                          Substituent                                      Monosaccharide Residue       on the                                           M.sub.2         Cyclic Radical                                                                             Cyclic Radical                                   ______________________________________                                        3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   4'-piperidyl H                                                 .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-piperidyl methyl, H                                         .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   2'-piperidyl "                                                 .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-pyrrolidyl                                                                              "                                                 .sub.--D-glucofuranose                                                       3- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   2'-pyrrolidyl                                                                              "                                                 .sub.--D-glucofuranose                                                       6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   4'-piperidyl H                                                 .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylene-                                                     3'-piperidyl methyl, H                                         .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   2' -piperidyl                                                                              "                                                 .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   3'-pyrrolidyl                                                                              "                                                 .sub.--D-galactopyranose                                                     6- .sub.--O--1,2- .sub.--O--isopropylidene-                                                   2'-pyrrolidyl                                                                              "                                                 .sub.--D-galactopyranose                                                     3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       4'-piperidyl H                                                propylidene-D-                                                                glucofuranose                                                                 3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       3'-piperidyl methyl, H                                        propylidene-D-                                                                glucofuranose                                                                 3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       2'-piperidyl "                                                propylidene-D-                                                                glucofuranose                                                                 3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       3'-pyrrolidyl                                                                              "                                                propylidene-D-                                                                glucofuranose                                                                 3- .sub.--O--1,2:3,6-di- .sub.--O--iso-                                                       2'-pyrrolidyl                                                                              "                                                propylidene-D-                                                                glucofuranose                                                                 6- .sub.--O--1,2:1,4-di- .sub.--O--iso-                                                       4'-piperidyl H                                                propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:1,4-di- .sub.--O--iso-                                                       3'-piperidyl methyl, H                                        propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.-- O--1,2:1,4-di- .sub.--O--iso-                                                      2'-piperidyl "                                                propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:1,4-di- .sub.--O--iso-                                                       3'-pyrrolidyl                                                                              "                                                propylidene- .sub.--D-                                                        galactopyranose                                                               6- .sub.--O--1,2:1,4-di- .sub.--O--iso-                                                       2'-pyrrolidyl                                                                              "                                                propylidene- .sub.--D-                                                        galactopyranose                                                               ______________________________________                                    

In general, the preparation of compounds of the formula M₁ --O--Ydescribed herein involves the formation of cyclic organo amine ethers oralkyl amine ethers of substituted cyclic organo amine ethers or alkylamine ethers at selected positions on the desired nonderivatizedmonosaccharide, such as at position 1-O- or 3-O- or D-glucose, position6-O- of D-galactose, and position 3-O- of D-fructose. Similarly, thepreparation of compounds of the formula M₂ --O--Y described hereininvolves the formation of the aforementioned types of ethers at selectedpositions on the desired monosaccharide derivative, such as at position3-O- or 1,2-O-isopropylidene-D-glucofuranose or1,2:5,6-di-O-isopropylidene-D-glucofuranose, position 6-O- of1,2-O-isopropylidene-D-galactopyranose or1,2:3,4-di-O-isopropylidene-D-galactopyranose, and position 3-O- of1,2-O-isopropylidene-D-fructopyranose or1,2:5,6-di-O-isopropylidene-D-fructopyranose. The condensation of thesubstituent substrate with the desired nonderivatized monosaccharide orthe monosaccharide derivative at the desired position may be achieved byvarious prior art techniques. One method is described in U.S. Pat. No.2,715,121, issued Aug. 9, 1955, to Glen, et al, the disclosure of whichis incorporated herein by reference. The method described in this patentrequires extreme reaction conditions and often gives low yields. Theproduct purity is also less than satisfactory.

The preferred method of preparation is described in my U.S. Pat. No.4,056,322, the disclosure of which is incorporated herein by reference,and involves much milder reaction conditions than employed in U.S. Pat.No. 2,715,121. The side reactions are minimized, the purity of the finalproduct is greatly improved and the method may be adapted to a series ofsolvents having varying properties such as dioxane, tetrahydrofuran andbenzene. The improved method involves the reaction of a monosaccharidederivative which is blocked with one or more organo groups in thehydroxyl group positions adjacent the desired position to besubstituted. The blocked monosaccharide is dissolved in one of theforegoing solvents and is reacted with a halogenated organo aminocompound having the desired carbon chain length and configuration in thepresence of a base such as sodium hydroxide. The resulting products arecompounds of the formula M₂ --O--Y, which are blocked derivatives of thecompounds M₁ --O--Y of the invention. Selective removal of one or moreblocking groups may be accomplished by hydrolysis under specificconditions resulting in a new product which is to be considered acompound suitable for use in this invention. The reaction of either theblocked compound or the hydrolyzed compound with organic or inorganicacids to form a salt thereof also results in a compound suitable for usein this invention.

It is understood that simple derivatives of the compounds describedherein may be used in practicing the invention. Such derivatives may beprepared by prior art techniques and procedures. For example, the freeamine compounds are basic and form organic acid salts and inorganic acidsalts, and the resulting salts are useful in the method of theinvention. The salts may be prepared by the usual prior art techniques,such as by adding the free amine compound to water and then adding thedesired organic acid or mineral acid thereto in an amount sufficient toneutralize the free amine. Examples of suitable acids include HCl, HBr,H₂ SO₄, HNO₃, benzoic acid, p-aminobenzoic acid, p-acetamidobenzoicacid, p-hydroxybenzoic acid, alkane sulfonic acids, p-toluene sulfonicacid, acetic acid, alkylcarboxylic acids, oxalic acid, tartaric acid,lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid andglucuronic acid. The aqueous solution of the resulting salt isevaporated to the volume necessary to assure precipitation of the saltupon cooling. The precipitated salt is recovered by filtration washedand dried to obtain a final amine salt product. The amine salts areoften preferred for use in formulating the therapeutic compositions ofthe invention as they are crystalline and relatively nonhygroscopic. Theamine salts are also better adapted for intramuscular injection than arethe free amines.

Prior art blocking or derivatizing techniques may be employed such asacetonization and acetylation. Suitable prior art blocking orderivatizing methods are described in the aforementioned U.S. Pat. Nos.2,715,121 and 4,056,322. The alcohols used to produce an acetal groupmay contain 1-18 and preferably 1-4 carbon atoms. Specific examplesinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, andisoamyl alcohols. In instances where an aldehyde or ketone is reactedwith hydroxyl groups on adjacent carbon atoms, the initial compound maybe dissolved in the desired aldehyde or ketone under anhydrousconditions and a Lewis acid catalyst is added in a catalytic quantity,such as 1% zinc chloride or anhydrous phosphoric acid. Often acetone isthe preferred blocking or derivatizing agent, but aldehydes or ketonesof much higher molecular weight may be used when desired such as thosecontaining up to 18 carbon atoms and preferably 1-8 or about 2-4 carbonatoms. Specific examples of additional ketones include methyl ethylketone, diethyl ketone, ethyl propyl ketone and dipropyl ketone.Specific examples of aldehydes include acetaldehyde, propionaldehyde,and butyraldehyde. The reaction mixture is agitated at room temperaturefor a prolonged reaction period, such as 24-48 hours. The compound maybe blocked or derivatized in a plurality of positions, such as the 1,2-and 5,6-positions. It is usually preferred to block or derivatizepositions such as the 1,2-positions as the resulting partially blockedor derivatized compound is much less toxic than compounds blocked orderivatized in all available hydroxyl groups.

It is also possible to block or derivatize one or more free hydroxylpositions of the compound with an ester group, wherein the carboylicacid residue contains 1-18 and preferably about 1-3 carbon atoms.Specific examples of organic acids include formic acid, acetic acid,propionic acid and butyric acid. The ester derivatives likewise may beprepared following prior art techniques such as by reacting a carboxylicacid anhydride with the compound following prior art practices.Additionally, the α or β alkyl derivatives of nonderivatizedmonosaccharides or of monosaccharide derivatives such as2,3:5,6-di-O-isopropylidene-D-glucofuranoside may be prepared followingprior art techniques. In this latter instance, the compound is dissolvedin a dry alcohol having the desired carbon chain length with theaforementioned residua and reacted with the compound in the presence ofa catalyst such as the hydrogen chloride of Dowax 5- H+ resin. While theabove discussed derivatives are presently preferred, it is understoodthat still other simple derivatives may be prepared following prior arttechniques and then used in practicing the present invention.

The groups used in derivatizing M₂ of the formula M₂ --O--Y arepreferably labil organo groups, such as acetal or ketal groups, whichare easily hydrolyzable or otherwise easily removed from the residue ofthe monosaccharide. For best results, the derivatizing groups should beeasily removed in situ following administering the compound M₂ --O--Y toa warm blooded animal to thereby produce the active compound M₁ --O--Y.

The compounds used in the method of the present invention may beadministered to human patients or lower warm blooded animals to betreated either orally or by parenteral administration, and either withor without a pharmaceutically acceptable carrier. When the compound isto be administered orally, it may be admixed with a prior art fillerand/or binder such as starch and a disintegrator, and the admixture maybe pressed into a tablet of a size convenient for oral administration.Capsules also may be filled with a composition containing the compound,with or without a filler, and administered orally. Alternatively, awater solution or suspension of the compound, or an admixture thereofwith a flavored syrup such as cherry syrup, may be administered orally.When the compound is administered by intramuscular injection, it isusually dissolved in a physiological saline solution which containssodium chloride in sufficient concentration to make the overall solutionto be injected isotonic to body fluids. A salt of the free amine isusually preferred in instances where the compound is administered byintramuscular injection. In treating some patients or when convenient,the salt form of the compound is aqueous solution may also beadministered by nasopharyngeal spray. Administration also may be bymeans of a suppository in patients unable to retain medicationadministered by mouth. Suitable pharmaceutically acceptable carriers andtechniques in addition to those mentioned above may be used whendesired.

The dosage may be varied over extremely wide limits, as the compoundsare effective at low dosage levels and are nontoxic and free of adverseside effects. The compounds may be administered in the minimum quantitywhich is effective, and the dosage may be increased as desired up to themaximum effective dosage tolerated by the patient. Animal toxicity dataindicate that the limiting nontoxic dosage may be 100-1000 or more timesthe minimum effective dosage. As a general rule, oral drug toxicity doesnot appear until the dosage exceeds 10 grams per kilogram of body weightper day and thus it is not necessary to carefully control the dosage forpatients sensitive to the prior art drugs. The compound is usuallyadministered in an amount of about 0.001-1000 milligrams, or for betterresults about 0.01-500 milligrams, per kilogram of body weight per day,and preferably in an amount of about 0.1-100 milligrams per kilogram ofbody weight per day, over the period required for treatment. In someinstances better results are obtained at dosage levels of about 1-20milligrams, and best results at about 10 milligrams, per kilogram ofbody weight per day.

In accordance with a further variant of the invention, a novelsynergistic composition is provided for use in the method of theinvention in treating autoimmune diseases in warm blooded animals whichincludes therapeutically active ingredients I and II. The ingredient Iis a substance selected from the previously described group consistingof ethereally monosubstituted monosaccharides having the formula M₁--O--Y, and/or an ethereal monosubstitution of monosaccharidederivatives having the formula M₂ --O--Y; and/or pharmaceuticallyacceptable organic acid and inorganic acid salts thereof. Thus, theingredient I is a compound as previously discussed and referencetherefor may be had to the foregoing discussion. The ingredient II is aprior art substance known to be therapeutically effective to treatautoimmune diseases when administered alone to the warm blooded animal,and which is therapeutically compatible with ingredient I and forms asynergistic composition therewith.

Examples of suitable prior art drugs which are therapeutically effectivein the treatment of autoimmune diseases such as the specific diseasesand drugs therefor previously discussed, are well known and there are anumber of publications on the subject. Reference may be had, forexample, to authoritative publications on this subject, such as thePhysicians Desk Reference, 31st Edition, published by Medical Economics,Oradell, N.J. (1977); The Merck Index, 9th Edition, edited by M.Windholz, published by Merck and Company, Inc., Raleigh, N.J. (1976);and Pharmacological Basis of Therapeutics, edited by Louis S. Goodman,et al, 4th Edition, published by MacMillan and Co., New York, (1970),the disclosures of all of which are incorporated herein by reference.These authoritative publications give the prior art medications whichare useful for autoimmune diseased, the quantity of medication to begiven, and the method of administering the medication. Thus, a personskilled in this art may by reference thereto select a medication, amountof the medication, and method of administering the medication, and thencombine these prior art teachings with the teachings of the presentinvention in arriving at a synergistic composition for use in thepresent invention.

As a general rule, the active ingredients of the synergistic compositionmay contain on a weight basis about 5-95%, and preferably about 25-75%,and usually for best results approximately 45-55% of ingredient I, andthe remainder ingredient II. It is understood that pharmaceuticallyacceptable carriers, fillers, and the like may be present as wasdiscussed previously when ingredient I is administered alone. Also, thecomposition may be administered in accordance with the same proceduresas discussed previously for ingredient I when used alone. The method ofadministering the synergistic composition also may be in accordance withthe above mentioned authoriative texts when using ingredient II alone.The dosage level when using the synergistic composition may be such asto provide the same amount of ingredient I as discussed hereinbeforewhen using ingredient I alone, and/or the same amount of ingredient IIas discussed in the authoriative texts. The synergistic compositionshould be administered in an amount to provide a quantity of ingredientII not in excess of the weight thereof recommended in the authoriativetexts, but smaller amounts are usually effective such as approximately5-75% or 10-60%, and preferably about 25-50% by weight of the quantitypreviously recommended. Inasmuch as ingredient II is much more toxicthan the compounds of ingredient I, it is possible to achive comparableor much better therapeutic results with the synergistic composition atthe same or lower level of toxicity. Markedly better therapeutic resultsare achieved at substantially the same toxicity level when using thefull recommended dose of the much more toxic ingredient II and the fullrecommended dose of the non-toxic ingredient I. However, lower amountsof each may be used with a corresponding drop in the toxicity levelthereby allowing effective therapeutic treatment to be given to patientswhich are sensitive to the prior art medications.

In view of the foregoing, it is apparent that the synergisticcompositions of the present invention, as well as the variant of themethod of the invention which utilizes the synergistic composition,produce many unusual and unexpected beneficial results. The prior artmedications may be used in smaller amounts to gain their benefits ininstances where the patient is sensitive thereto, and yet still obtainthe full benefits of the non-toxic compounds of ingredient I.Surprisingly, the compounds of ingredient I are not only non-toxic andfree of side effects, but they are also compatible with the prior artdrugs. Thus ingredient I may be administered in combination withingredient II without noticeably increasing the overall toxicity levelor otherwise adversely affecting the patient.

The aforementioned compounds of ingredient I alone or the overallsynergistic composition may be administered either before, during orafter appearance of the symptoms of the autoimmune disease. In someinstances, it is preferred that the patient be treated eitherpermanently or throughout the period of time necessary to prevent orsuppress symptoms. This procedure is essentially effective in thetreatment of rheumatoid arthritis, wherein it is often preferred thatpatients be placed on a chronic dose of medication throughout the winteror other seasons when the symptoms are aggravated. The method of theinvention is also very effective in treating acute attacks of autoimmunediseases.

The method and composition of the invention are especially useful intreating human patients, but lower warm blooded animals and especiallylower mammals also may be treated. For example, domestic animals andpets such as horses, bovines in general, sheep, goats, swine, cattle,poultry, birds and fowls in general, dogs, cats and the like may betreated in accordance with the invention. The foregoing are collectivelyreferred to herein as being warm blooded animals.

The invention is further illustrated by the following hypotheticalexamples.

EXAMPLE I

It is known that female NZB/W mice develop an autoimmune diseasecharacterized by immune complex glomerulonephritis, antibodies to DNAand RNA, lupus erythematosus (LE) cells, and shortened life expectancy.These findings are also seen in human systemic lupus erythrmatosus.

In this study, female NZB/W mice, age 20 weeks and already manifestingautoimmunity, are given SM-1211 or SM-1213 ad libitum in the drinkingwater at concentrations of either 0.1 or 0.01 mg/ml over ten weeks, andthe frequency of proteinuria and antibodies to DNA are monitored byprior art techniques. The drugs should significantly reduce bothsymptoms of autoimmune disease, a finding which would be significantbecause of the relationship of this animal disease model to humanautoimmune pathology.

EXAMPLE II

Twenty-four patients with classical or definite long-standing rheumatoidarthritis who respond poorly to the usual antiinflammatory and analgesicdrugs are divided into a placebo group and two drug treatment groups,and are treated for six months. None of these patients have receivedcorticosteroids, antimalarials, cytostatic agents or gold compounds forsix months prior to the study, and are removed from antiinflammatory andanalgesic drugs during the period of the study. SM-1211 and SM-1213 areadministered as 20 mg/kg two times daily. The results of this studyshould show that drug treatment with SM-1211 and SM-1213 strikinglyreduces the number of active joints and reduces the sedimentation ratein all cases.

EXAMPLE III

The procedure described in EXAMPLE II is carried out again, except thatduring the period of the study the antiinflammatory and analgesictherapies are continued unchanged. The results of this study should showthat treatment with SM-1211 or SM-1213 in combination withantiinflammatory and analgesic therapies strikingly reduces the numberof active joints and reduces the sedimentation rate.

I claim:
 1. A method of therapeutically treating a warm blooded animalafflicted with an autoimmune disease selected from the group consistingof rheumatoid arthritis, rheumatic fever, eczema or lupus erythematosiswhich consists essentially ofadministering to said warm blooded animalan amount effective to therapeutically treat the rheumatoid arthritis,rheumatic fever, eczema or lupus erythematosis of a compound selectedfrom the group consisting ofI. ethereally monosubstitutedmonosaccharides having the formula M₁ --O--Y and therapeuticallyeffective and pharmaceutically acceptable organic acid and inorganicacid salts thereof, and II. etheral monosubstitutions of monosaccharidederivatives having the formula M₂ --O--Y and therapeutically effectiveand pharmaceutically acceptable organic acid and inorganic acid saltsthereof, wherein:(1) M₁ is the residue of a non-derivatized hexose, (2)M₂ is the residue of a hexose which has been derivatized with asubstance selected from the group consisting of(a) an alcohol containing1-18 carbon atoms to produce an ether group at the site of an availablehydroxyl residue, (b) an aldehyde containing 1-18 carbon atoms toproduce an acetal group at site of an available hydroxy residue, (c) aketone containing 1-18 carbon atoms to produce a ketal group at the siteof an available hydroxyl residue, and (d) an organic acid residuecontaining 1-18 carbon atoms to produce an ester group at the site of anavailable hydroxyl residue, and (3) Y in each instance is selected fromthe group consisting of (a) piperidyl and pyrrolidyl, and (b) monovalentorganic radicals having the formula ##STR6## wherein R₁ is a divalentorganic radical having a carbon chain length of 1-4 carbon atoms and R₂and R₃ are selected from the group consisting of hydrogen and monovalentorganic radicals having a carbon chain length of 1-4 carbon atoms. 2.The method of claim 1 wherein Y of said compound is ##STR7## R₁ is ahydrocarbon having a carbon chain length of 1-3 carbon atoms, R₂ and R₃are selected from the group consisting of hydrogen and hydrocarbonshaving a carbon chain length of 1-3 carbon atoms, and M₁ and M₂ areglucose or galactose.
 3. The method of claim 1 wherein said compound is3-O-3'-(N',N'-dimethylamino-n-propyl)-glucose or3-O-3'-(N',N'-dimethylamino-n-propyl)-1,2-O-isopropylidene-glucose. 4.The method of claim 1 wherein said compound is3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose or3-O-3'-(N',N'-dimethylamino-n-propyl)-D-1,2-O-isopropylideneglucofuranose.
 5. The method of claim 2, wherein said compound is in theform of a salt of an acid selected from the group consisting of HCl,HBr, H₂ SO₄, HNO₃, benzoic acid, p-aminobenzoic acid, p-acetamidobenzoicacid, p-hydroxybenzoic acid, alkane sulfonic acid, p-toluene sulfonicacid, lower alkyl monocarboxylic acids, oxalic acid, tartaric acid,lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid andglucuronic acid.
 6. The method of claim 1, wherein said compound is inthe form of a salt of an acid selected from the group consisting of HCl,HBr, H₂ SO₄, HNO₃, benzoic acid, p-aminobenzoic acid, p-acetamidobenzoicacid, p-hydroxybenzoic acid, alkane sulfonic acid, p-toluene sulfonicacid, lower alkyl monocarboxylic acids, oxalic acid, tartaric acid,lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid andglucuronic acid.
 7. The method of claim 4, wherein said compound is inthe form of a salt of an acid selected from the group consisting of HCl,HBr, H₂ SO₄, HNO₃, benzoic acid, p-aminobenzoic acid, p-acetamidobenzoicacid, p-hydroxybenzoic acid, alkane sulfonic acid, p-toluene sulfonicacid, lower alkyl monocarboxylic acids, oxalic acid, tartaric acid,lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid andglucuronic acid.
 8. The method of claim 7 wherein said autoimmunedisease is rheumatoid arthritis.
 9. The method of claim 2 wherein saidautoimmune disease is rheumatoid arthritis.
 10. The method of claim 4wherein said autoimmune disease is rheumatoid arthritis.
 11. The methodof claim 2 wherein said autoimmune disease is rheumatic fever.
 12. Themethod of claim 3 wherein said autoimmune disease is rheumatic fever.13. The method of claim 4 wherein said autoimmune disease is rheumaticfever.
 14. The method of claim 2 wherein said autoimmune disease iseczema.
 15. The method of claim 3 wherein said autoimmune disease iseczema.
 16. The method of claim 4 wherein said autoimmune disease iseczema.
 17. The method of claim 2 wherein said autoimmune disease islupus erythematosis.
 18. The method of claim 3 wherein said autoimmunedisease is lupus erythematosis.
 19. The method of claim 4 wherein saidautoimmune disease is lupus erythematosis.